rs142894102

Positions:

chr1-40092078-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5

The NM_000310.4(PPT1):c.329A>G(p.Asn110Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N110D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

PPT1
NM_000310.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:9

Conservation

PhyloP100: 7.83

Variant links:

Genes affected

PPT1 (HGNC:9325): (palmitoyl-protein thioesterase 1) The protein encoded by this gene is a small glycoprotein involved in the catabolism of lipid-modified proteins during lysosomal degradation. The encoded enzyme removes thioester-linked fatty acyl groups such as palmitate from cysteine residues. Defects in this gene are a cause of infantile neuronal ceroid lipofuscinosis 1 (CLN1, or INCL) and neuronal ceroid lipofuscinosis 4 (CLN4). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2008]

PPT1 links:

PPT1 (HGNC:):

PPT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000310.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-40092077-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3015048.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 1-40092078-T-C is Pathogenic according to our data. Variant chr1-40092078-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196249.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPT1	NM_000310.4 linkuse as main transcript	c.329A>G	p.Asn110Ser	missense_variant	3/9	ENST00000642050.2	NP_000301.1	P50897-1
PPT1	NM_001363695.2 linkuse as main transcript	c.329A>G	p.Asn110Ser	missense_variant	3/8		NP_001350624.1
PPT1	NM_001142604.2 linkuse as main transcript	c.125-2566A>G		intron_variant			NP_001136076.1	P50897-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2 linkuse as main transcript	c.329A>G	p.Asn110Ser	missense_variant	3/9		NM_000310.4	ENSP00000493153.1		P50897-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000187

AC:

AN:

251452

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000195

AC:

285

AN:

1461794

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

156

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000429

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000194

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000118

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000181

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1

Pathogenic:3Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 110 of the PPT1 protein (p.Asn110Ser). This variant is present in population databases (rs142894102, gnomAD 0.06%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 30541466). ClinVar contains an entry for this variant (Variation ID: 196249). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PPT1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 13, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed missense c.329A>G (p.Asn110Ser) variant in PPT1 gene has been reported previously in multiple individuals affected with PPT1-related disorders (Sheth et al., 2018; Atli et al., 2022; Ozturk et al., 2022). The p.Asn110Ser variant is present with allele frequency of 0.02% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic/ Uncertain Significance (multiple submissions). Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Asn110Ser in PPT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asn at position 110 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 19, 2024	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2024	Reported in the heterozygous state in a patient with cognitive impairment, ADHD, and epilepsy in the published literature; however, a second PPT1 variant was not identified (PMID: 33528079); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a homozygous state in a patient with episodic torticollis and sudden cardiac arrest who also harbored another homozygous variant in a gene related to the phenotype (PMID: 35693655); This variant is associated with the following publications: (PMID: 34426522, 35693655, 30541466, 33528079, Bhavsar2016[CaseReport]) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2014	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 26, 2023

Variant summary: PPT1 c.329A>G (p.Asn110Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251452 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PPT1 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (0.00019 vs 0.0014), allowing no conclusion about variant significance. c.329A>G has been reported in the literature in the homozygous state in an individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) who had significantly reduced PPT1 enzyme activity compared to normal controls (Sheth_2018). These data indicate that the variant may be associated with disease. However, it has also been reported in the homozygous state in an individual from a consanguineous family, affected with Childhood Onset Neurodegeneration with Ataxia and Seizures, who had a normal PPT1 level and was also homozygous for a variant in the ADPRHL2 gene (c.235A>C, p.T79P) which may explain the phenotype (Ozturk_2022). Finally, the variant has also been reported as a heterozygous genotype in an individual affected with cognitive impairment, ADHD, and epilepsy (Atli_2022). Thus, these reports do not allow for any strong conclusions to be made about variant significance. The following publications have been ascertained in the context of this evaluation (PMID: 33528079, 30541466, 35693655). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=7) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2021

The c.329A>G (p.N110S) alteration is located in exon 3 (coding exon 3) of the PPT1 gene. This alteration results from a A to G substitution at nucleotide position 329, causing the asparagine (N) at amino acid position 110 to be replaced by a serine (S). The in silico prediction for the p.N110S alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual disability

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;.;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

.;D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.49

T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

H;.;.;.;.

PrimateAI

Uncertain

0.50

REVEL

Pathogenic

0.78

Polyphen

1.0

D;.;.;.;.

MVP

0.98

MPC

0.50

ClinPred

0.30

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over